Donor Umbilical Cord Blood Transplant With or Without Ex-vivo Expanded Cord Blood Progenitor Cells in Treating Patients With Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, or Myelodysplastic Syndromes

• ClinicalTrials.gov Identifier: NCT01690520
• Recruitment Status: Unknown
• First Posted: September 21, 2012
• Last Update Posted: April 1, 2019
• Sponsor: Nohla Therapeutics, Inc.
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Nohla Therapeutics, Inc.

Tracking Information

• First Submitted Date: September 19, 2012
• First Posted Date: September 21, 2012
• Last Update Posted Date: April 1, 2019
• Actual Study Start Date: December 11, 2012
• Actual Primary Completion Date: September 18, 2018 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: March 28, 2019): Time to neutrophil engraftment [ Time Frame: Up to 55 days post-transplant ]

Original Primary Outcome Measures (submitted: September 19, 2012)

Time to engraftment (ANC greater than or equal to 500) in both arms (standard myeloablative CBT with and without off-the-shelf expanded cord blood progenitors) [ Time Frame: Up to 2 years ]

The log-rank test will be used.

Current Secondary Outcome Measures (submitted: March 28, 2019)

• Time to platelet engraftment (20k) [ Time Frame: Up to 100 days post-transplant ]
• Overall survival [ Time Frame: Up to 2 years ]
• Non-relapse mortality [ Time Frame: Up to 2 years ]
• Incidence of severe acute graft versus host disease [ Time Frame: Up to 100 days post-transplant ]
• Incidence of chronic graft versus host disease [ Time Frame: Up to 2 years ]

Original Secondary Outcome Measures (submitted: September 19, 2012)

• Time to engraftment, defined as the first of 2 consecutive days in which ANC is at least 500 [ Time Frame: Up to 2 years ]
• Relative contribution to engraftment of the expanded cord blood product and the unmanipulated cord blood unit(s) in early and long-term engraftment, determined by frequent determination of donor chimerism in the peripheral blood [ Time Frame: Up to 2 years ]
• Time to ANC greater than or equal to 100 [ Time Frame: Up to 2 years ]
• Time to ANC greater than or equal to 500 [ Time Frame: Up to 2 years ]
• Time to platelet engraftment (20k) [ Time Frame: Up to 2 years ]
• Time to platelet engraftment (50k) [ Time Frame: Up to 2 years ]
• Duration of initial hospitalization [ Time Frame: Up to 2 years ]
• Incidence of infectious complications [ Time Frame: Up to 100 days post-transplant ]
• Non-relapse mortality (NRM) [ Time Frame: Day 200 ]
• NRM [ Time Frame: 1 year ]
• Incidence and severity of acute and chronic GVHD [ Time Frame: Up to 2 years ]
• Infusional toxicity greater than or equal to grade 3 [ Time Frame: Up to 2 years ]
• Graft failure (primary and secondary) [ Time Frame: Up to 2 years ]
• Kinetics of immune system recovery as measured by T and B cell subsets, T cell receptor excision circles (TREC), spectratyping and T cell receptor (TCR) sequencing [ Time Frame: Up to 2 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Donor Umbilical Cord Blood Transplant With or Without Ex-vivo Expanded Cord Blood Progenitor Cells in Treating Patients With Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, or Myelodysplastic Syndromes
• Official Title: Multi-Center, Open-Label Randomized Study of Single or Double Myeloablative Cord Blood Transplantation With or Without Infusion of Off-The-Shelf Ex Vivo Expanded Cryopreserved Cord Blood Progenitor Cells in Patients With Hematologic Malignancies
• Brief Summary: This randomized phase II trial studies how well donor umbilical cord blood transplant with or without ex-vivo expanded cord blood progenitor cells works in treating patients with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, or myelodysplastic syndromes. Giving chemotherapy and total-body irradiation before a donor umbilical cord blood transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's cells. When the healthy stem cells and ex-vivo expanded cord blood progenitor cells are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. It is not yet known whether giving donor umbilical cord blood transplant plus ex-vivo expanded cord blood progenitor cells is more effective than giving a donor umbilical cord blood transplant alone.

Detailed Description

PRIMARY OBJECTIVES:

I. Compare the time to neutrophil engraftment (absolute neutrophil count [ANC] >= 500) in patients receiving a standard of care myeloablative cord blood transplant (CBT) augmented with an off-the-shelf pre-expanded and cryopreserved cord blood product to those who do not receive the product.

SECONDARY OBJECTIVES:

I. Provide initial data on clinical and economic benefit, such as time to platelet engraftment, duration of initial hospitalization, transplant-related mortality (TRM), death without engraftment, and incidence of severe infections in the first 100 days post-transplant.

II. The kinetics of immune system recovery will also be evaluated in both arms.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

Standard of Care Arm:

CONDITIONING REGIMEN: One of two possible conditioning regimens is chosen by the attending physician: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 to -6., and undergo high dose total-body irradiation (TBI) twice daily (BID) on days -4 to -1 OR, patients receive fludarabine phosphate IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 4 hours on days -5 to -4, and undergo middle intensity TBI once daily (QD) on days -2 to -1.

TRANSPLANT: Patients undergo single-unit or double-unit unmanipulated umbilical cord blood (UCB) transplant on day 0.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive cyclosporine IV over 1 hour BID (adults) or thrice daily (TID) (children) or orally (PO) on days -3 to 100 with taper beginning on day 101. Patients also receive mycophenolate mofetil (MMF) IV TID on days 0-7 then may receive MMF PO TID. Patients remain on MMF TID for a minimum of 30 days, and then may begin taper if there is no evidence of GVHD and are well-engrafted from one donor unit.

Experimental Arm:

CONDITIONING REGIMEN: Patients receive the conditioning regimen chosen by the attending physician as in Standard of Care Arm.

TRANSPLANT: Patients undergo single-unit or double-unit unmanipulated UCB transplant on day 0. Patients also receive an infusion of ex vivo-expanded cord blood progenitors at least 4 hours after completion of UCB transplant.

GVHD PROPHYLAXIS: Patients receive cyclosporine IV or PO and mycophenolate mofetil IV or PO as in Standard of Care Arm.

After completion of study treatment, patients are followed up periodically for 2 years.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Acute Biphenotypic Leukemia
• Acute Lymphoblastic Leukemia in Remission
• Acute Myeloid Leukemia in Remission
• Chronic Myelogenous Leukemia
• Myelodysplastic Syndrome

Intervention

• Drug: Cyclophosphamide
  Given IV
• Drug: Cyclosporine
  Given IV or PO
• Biological: Ex Vivo-Expanded Cord Blood Progenitor Cell Infusion
  Given IV
  Other Names:

  • NLA101
  • Dilanubicel
• Drug: Fludarabine Phosphate
  Given IV
• Drug: Mycophenolate Mofetil
  Given IV or PO
• Drug: Thiotepa
  Given IV
• Radiation: Total-Body Irradiation
  Undergo high dose or middle intensity TBI
• Procedure: Umbilical Cord Blood Transplantation
  Undergo single-unit or double-unit unmanipulated umbilical cord blood transplant
  Other Names:

  • Cord Blood Transplantation
  • UCB transplantation

Study Arms

• Active Comparator: Arm I (standard of care)

  CONDITIONING REGIMEN: One of two possible conditioning regimens is chosen by the attending physician: Patients receive fludarabine phosphate IV over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 to -6., and undergo high dose TBI BID on days -4 to -1 OR Patients receive fludarabine phosphate IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 4 hours on days -5 to -4, and undergo middle intensity TBI QD on days -2 to -1.

  TRANSPLANT: Patients undergo single-unit or double-unit unmanipulated UCB transplant on day 0.

  GVHD PROPHYLAXIS: Patients receive cyclosporine IV over 1 hour BID (adults) or TID (children) or PO on days -3 to 100 with taper beginning on day 101. Patients also receive MMF IV TID a day on days 0-7 then may receive MMF PO TID. Patients remain on MMF TID for a minimum of 30 days, and then may begin a taper if there is no evidence of GVHD and are well-engrafted from one donor unit.

  Interventions:

  • Drug: Cyclophosphamide
  • Drug: Cyclosporine
  • Drug: Fludarabine Phosphate
  • Drug: Mycophenolate Mofetil
  • Drug: Thiotepa
  • Radiation: Total-Body Irradiation
  • Procedure: Umbilical Cord Blood Transplantation
• Experimental: Arm II (experimental)

  CONDITIONING REGIMEN: Patients receive the conditioning regimen chosen by the attending physician as in Standard of Care Arm.

  TRANSPLANT: Patients undergo single-unit or double-unit unmanipulated UCB transplant on day 0. Patients also undergo infusion of ex vivo-expanded cord blood progenitor cell infusion at least 4 hours after completion of UCB transplant.

  GVHD PROPHYLAXIS: Patients receive cyclosporine IV or PO and mycophenolate mofetil IV or PO as in Standard of Care Arm.

  Interventions:

  • Drug: Cyclophosphamide
  • Drug: Cyclosporine
  • Biological: Ex Vivo-Expanded Cord Blood Progenitor Cell Infusion
  • Drug: Fludarabine Phosphate
  • Drug: Mycophenolate Mofetil
  • Drug: Thiotepa
  • Radiation: Total-Body Irradiation
  • Procedure: Umbilical Cord Blood Transplantation

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Actual Enrollment (submitted: March 28, 2019): 163
• Original Estimated Enrollment (submitted: September 19, 2012): 160
• Study Completion Date: Not Provided
• Actual Primary Completion Date: September 18, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age criteria:

  • High dose TBI regimen: 6 months to =< 45 years
  • Middle intensity TBI regimen: 6 months to =< 65 years
  • Conditioning regimen selection should be based on the underlying disease, presence of minimal residual disease (MRD), age, co-morbidities, attending physician, and site preference; conditioning regimen will not require stratification of the randomization due to heterogeneity in the cohort of eligible patients.

• Acute myeloid leukemia, including biphenotypic acute leukemia or mixed-lineage leukemia

  • All patients must have acute myeloid leukemia (AML) that is considered best treated by stem cell transplant by the referring physician and the attending transplant physician
  • All patients must be in complete remission (CR) as defined by < 5% blasts by morphology/flow cytometry in a representative bone marrow sample with cellularity >= 15% for age
  • Patients in which adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible; reasonable attempts must be made to obtain an adequate specimen for morphologic assessment, including possible repeat procedures; these patients must be discussed with the principal investigator prior to enrollment

• Acute lymphoblastic leukemia, including biphenotypic acute leukemia or mixed-lineage leukemia

  • High risk first complete remission (CR1) (for example, but not limited to: t(9;22), t(1;19), t(4;11) or other mixed-lineage leukemia [MLL] rearrangements, hypodiploid); or high risk (HR) as defined by referring institution treatment protocol greater than 1 cycle to obtain CR; second complete remission (CR2) or greater
  • All patients must be in CR as defined by < 5% blasts by morphology/flow cytometry in a representative bone marrow sample with cellularity >= 15% for age
  • Patients in which adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible; reasonable attempts must be made to obtain an adequate specimen for morphologic assessment, including possible repeat procedures; these patients must be discussed with the principal investigator prior to enrollment
• Chronic myelogenous leukemia excluding refractory blast crisis; to be eligible in first chronic phase (CP1) patient must have failed or be intolerant to tyrosine kinase inhibitor therapy
• Myelodysplasia (MDS) International Prognostic Scoring System (IPSS) intermediate (Int)-2 or high risk (i.e., refractory anemia with excess blasts [RAEB], refractory anemia with excess blasts in transformation [RAEBt]) or refractory anemia with severe pancytopenia or high risk cytogenetics; blasts must be < 10% by a representative bone marrow aspirate morphology
• Karnofsky (>= 16 years old) >= 70 or Eastern Cooperative Oncology Group (ECOG) 0-1
• Lansky (< 16 years old) >= 60
• Adults: calculated creatinine clearance must be > 60 mL and serum creatinine =< 2 mg/dL
• Children (< 18 years old): calculated creatinine clearance must be > 60 mL/min
• Total serum bilirubin must be < 3 mg/dL unless the elevation is thought to be due to Gilbert's disease or hemolysis
• Transaminases must be < 3 x the upper limit of normal per reference values of referring institution
• Diffusing capacity of the lung for carbon monoxide (DLCO) corrected > 60% normal
• For pediatric patients unable to perform pulmonary function tests, oxygen (O2) saturation > 92% on room air
• May not be on supplemental oxygen
• Left ventricular ejection fraction > 45% OR
• Shortening fraction > 26%
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Uncontrolled viral or bacterial infection at the time of study enrollment
• Active or recent (prior 6 month) invasive fungal infection without infectious disease (ID) consult and approval
• History of human immunodeficiency virus (HIV) infection
• Pregnant or breastfeeding
• Prior myeloablative transplant containing full dose TBI (greater than 8 Gy)
• Central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy and/or cranial radiation prior to initiation of conditioning; diagnostic lumbar puncture is to be performed per protocol
• Patients >= 45 years: comorbidity score of 5 or higher

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months to 65 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01690520
• Other Study ID Numbers: 2603.00; NCI-2012-01572 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 2603; 2603.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ); P30CA015704 ( U.S. NIH Grant/Contract ); P50HL110787 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Nohla Therapeutics, Inc.
• Study Sponsor: Nohla Therapeutics, Inc.

Collaborators

• National Cancer Institute (NCI)
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Filippo Milano; Fred Hutch/University of Washington Cancer Consortium

• PRS Account: Nohla Therapeutics, Inc.
• Verification Date: March 2019